Mitochondria provide ATP to support normal cell function and their perturbation leads to apoptotic and necrotic cell death (Crompton, 1999). An important factor in apoptosis and necrosis is the mitochondrial permeability transition (MPT), which occurs as a result of calcium overload. The cause of the MPT is the opening of a non-specific pore in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore (MPTP) (Crompton et al., 1987). Oxidative stress, adenine nucleotide depletion and elevated inorganic phosphate greatly increase the sensitivity of the pore to calcium concentration. Opening of the MPTP is accompanied by equilibration of all small solutes (<1.5 kD) across the inner mitochondrial membrane. The resultant high protein concentration in the matrix exerts a colloidal osmotic pressure that is responsible for extensive swelling of mitochondria, and ultimately, apoptosis or necrosis.
Adenine nucleotide translocator (ANT) is a 30 kD protein that spans the inner mitochondrial membrane and is central to the MPTP (Crompton et al., 1988).
There is a need to selectively induce the MPT, particularly in proliferating cells, as a means of inducing apoptosis.
The present invention relates to a process for identifying compounds which bind to ANT in mitochondria and selectively induce the MPT in proliferating cells relative to non-proliferating or growth quiescent cells.